The long-term goal of this project is to better understand the environmental influence on brain aging and subsequent risk of cognitive impairment and dementia. Specifically, we will investigate later-life exposure to ambient air pollutants as novel environmental determinants of cognitive aging in a susceptible population of older women. Over the last decade, scientific research has repeatedly shown that ambient air pollution increases cardiovascular disease (CVD) risk and mortality. Previous studies have found that older people, especially women, are more sensitive to these adverse health effects of air pollutants. Although CVD is a major contributor to cognitive impairment and dementia, little attention has been directed to the potential impact of ambient air pollution on cognitive health of the elderly. Memory impairments have been demonstrated in animal models exposed to ozone. Neurotoxicological data have shown that exposures to ambient air pollutants induce oxidative stress and neuroinflammation in multiple brain regions, especially in hippocampus and prefrontal region. Air pollution toxicopathological studies also found evidence of accelerated brain aging (e.g., 2-amyloid accumulation with or without dystrophic neuritis) in canines. Human autopsy studies and cross-sectional epidemiologic analyses have related ambient air pollution to neuropathology of brain aging or cognitive impairment, respectively. Convincing cohort studies on whether and how ambient air pollution contributes to brain aging and subsequent risk of cognitive impairment and dementia in humans, however, are still lacking. The proposed study is thus designed in a cost-efficient manner to address this critical knowledge gap, through the following specific aims: (1) to examine whether later-life exposure to air pollution predicts declines in cognitive function (global; specific domains); (2) to investigate whether long-term air pollution exposure increases the risk of dementia; (3) to elucidate the possible mechanisms linking cognitive impairment with exposure to air pollution; and (4) to identify the clinical determinants of population susceptibility to the neurocognitive effects of air pollution. This application leverages the high-quality longitudinal outcome data collected in the well-characterized Women's Health Initiative Memory Study (WHIMS) cohort (N=7479; aged 65-80 years). Based on residential geocode of each WHIMS participant, exposures to particulate matter and ozone will be estimated by a spatiotemporal modeling approach, which integrates air-sample measurements from the U.S. EPA monitoring system with the data outputs of air quality models. Multivariable-adjusted Cox models, multilevel mixed-effect models, and latent curve structural models will be used to analyze the data. The knowledge gained from this study will contribute to national efforts to better understand the environmental influence on cognitive health, address a critical knowledge gap in the emerging area of environmental neurology, and inform the environmental public health policies.